tbuckley/cabot-search huggingface dataset:
Abstract 5794: Targeting CD133+/CD90+ liver cancer stem cells by piperlongumine: A novel strategy for liver cancer treatment
Authors: Basma A. Abdelaziz, Omayma M. Sadek, Ahmed S. Sultan
Journal: Cancer Research (2023)

Abstract Liver cancer is an aggressive malignant disease. It’s the most common cancer worldwide and the leading cause of cancer death. Because of the atypical early symptoms of liver cancer, the majority of liver cancer patients are diagnosed with advanced-cancer stage, decreasing the chance of resection and resulting in a poor survival rate. Liver cancer stem cells (LCSCs) are a small subpopulation inside the tumor bulk, characterized by the maintenance of self-renewal and pluripotency. Thus, LCSCs are responsible for cancer initiation, metastasis, relapse, and chemoresistance. Elucidating LCSC characteristics and disclosing their regulatory mechanism might facilitate the development of prognostic, diagnostic, and therapeutic approaches to improve the clinical management of liver cancer. Piperlongumine (PL) an active biological pyridine alkaloid has anti-angiogenic, anti-diabetic, and anti-bacterial activities. The present study aimed to isolate highly tumorigenic and aggressive subpopulation of LCSCs (CD133+/CD90+) from primary tumors and different cell lines and investigate the effect of (PL), a novel targeting therapy, on LCSCs proliferation. The isolated LCSCs were treated with different concentrations of PL and its effect was examined by cell viability, cell morphological changes, western blot, caspase-3 activity, apoptotic induction, and clonogenic formation. By using Immunocytochemistry (ICC) analysis, the localization of nuclear and cytoplasmic Aldehyde dehydrogenase (ALDH6A1) was detected. PL inhibited the viability of CD133+/CD90+LCSC-sub-popupation and caused morphological changes after 48 hours while enhancing the pre-apoptotic signals and caspase-3 activity. In addition, PL decreased the colonies’ formation ability compared to control group. Furthermore, PL suppressed the protein expression levels of ALDH6A1, Notch-1, β-catenin, ERK1/2, and Cyclin-D1 in the dose and time-dependent manners. Besides, PL decreased the localization and intensity of nuclear and cytoplasmic ALDH6A1 compared to the control group, indicating that PL decreased the proliferation and stemness markers of LCSCs. Overall, Piperlongumine as a novel targeting therapy has an important role in targeting CD133+/CD90+ LCSCs sub-population proliferation. Citation Format: Basma A. Abdelaziz, Omayma M. Sadek, Ahmed S. Sultan. Targeting CD133+/CD90+ liver cancer stem cells by piperlongumine: A novel strategy for liver cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5794.
Abstract 389: Focal adhension kinase (FAK) confers lenvatinib resistance in hepatocellular carcinoma via regulation of lysine deficient protein kinase 1(WNK1)
Authors: Wei Hou, Shaimaa A. Gad, Wei Qiu
Journal: Cancer Research (2023)

Abstract Lenvatinib is a clinically effective multi-kinase inhibitor approved for first-line therapy of advanced hepatocellular carcinoma (HCC). Although resistance against lenvatinib often emerges and limits its anti-tumor activity, the underlying molecular mechanisms involved in endogenous and acquired resistance are still unidentified. Endogenous (SNU449 and SNU475) and established acquired (Hep3B-LR and Huh7-LR) lenvatinib resistant cells, as well as knockout mice were used in this study. As a result, we recognized focal adhension kinase (FAK) as a critical contributor to lenvatinib resistance in HCC. The elevated expression of FAK was observed in both established and endogenous lenvatinib-resistant HCC cells. Furthermore, inhibition of FAK reversed lenvatinib resistance in vitro and in vivo. Mechanistically, FAK promoted lenvatinib resistance through regulating lysine deficient protein kinase 1 (WNK1) signaling pathway. WNK1 inhibitor WNK463 re-sensitized either established LR HCC cells (Hep3B-LR and Huh7-LR) or endogenous resistant HCC cells (SNU449 and SNU475) to lenvatinib treatment. In addition, overexpression of WNK1 desensitized parental HCC cells (Hep3B-P and Huh7-P) to lenvatinib treatment. Conclusively, our results establish a crucial role and novel mechanism of FAK in lenvatinib resistance, and suggest that targeting the FAK/WNK1 axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance. Citation Format: Wei Hou, Shaimaa A. Gad, Wei Qiu. Focal adhension kinase (FAK) confers lenvatinib resistance in hepatocellular carcinoma via regulation of lysine deficient protein kinase 1(WNK1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 389.
Abstract 4679: Molecular pathology and BTKi pharmacology of DLBCL-PDXs
Authors: Jingjing Wang, Yueying Wang, Wubin Qian, Jia Xue, Sheng Guo, Likun Zhang, Henry Qixiang Li
Journal: Cancer Research (2023)

Abstract Diffuse large B-cell lymphoma (DLBCL), the largest subtype of non-Hodgkin’s lymphoma (NHL, ~40%), is a heterogeneous disease with diverse pathogenesis, represented by different subtypes/genotypes based on lymphoma related specific gene expression profiling according to cell-of-origin (COO) and/or mutation profiles, likely influencing their responses to drug treatment. Patient derived xenografts (PDXs) represent powerful experimental system to investigate heterogeneous molecular pathology, and their corresponding pharmacology of DLBCLs. We created a unique cohort of 19 PDXs representative of diverse subtypes of de novo DLBCL patients, along with 15 EBV transformed DLBCLs during xenografting, followed by comprehensive molecular pathological analysis, using “EBV scan”, COO and LymphGen algorithm. The 19 de novo DLBCL-PDXs were classified into activated B cell-like (7/19 ABC, including 2 EBV+), germinal center B-cell-like (4/19 GCB) and unclassified (8/19 including 4 EBV+); the 15 EBV transformed DLBCL include two ABC, one GCB and 12 unclassified. The de novo DLBCL-PDXs were also annotated as MCD, BN2, N1, A53, ST2, and unknown genotypes. Clustering and principal component analysis (PCA) clearly separated EBV+ DLBCL-PDXs (regardless of de novo DLBCL, EBV-associated, or EBV transformed DLBCLs) from the EBV− de novo DLBCL-PDXs, suggesting distinct molecular pathogenesis, while no apparent difference between the two EBV+ DLBCLs suggested the similar pathogenesis. The expanded mouse clinical trial of BTKi using drinking water administration of ibrutinib (0.16mg/ml) showed: 1) EBV− MCD and BN2 genotype are largely sensitive, suggesting these models’ dependency of chronic BCR signaling; 2) all EBV+ DLBCLs, regardless of the origin or genotypes, are all insensitive; 3) there are some cases of EBV− non-MCD/BN2 models being sensitive, likely due to the presence of certain related activating mutations. Molecular pathology analysis also demonstrated EBV+ PDXs, including significantly elevated BCL2 and down-regulated BCL6, in contrast to EBV− DLBCL-PDXs, implicating possible sensitivity to respective treatments. In summary, these observations in PDXs, some of which are consistent with the retrospective analysis of clinical trials, can be used to help develop BTKi and other treatment for DLBCLs. Citation Format: Jingjing Wang, Yueying Wang, Wubin Qian, Jia Xue, Sheng Guo, Likun Zhang, Henry Qixiang Li. Molecular pathology and BTKi pharmacology of DLBCL-PDXs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4679.
Abstract 1357: Alpha-synuclein may promote melanoma progression by modulating the levels of tetraspanin proteins
Authors: Nirjhar Mandal Aloy, Michael W. Graner, Stephan N. Witt
Journal: Cancer Research (2023)

Abstract Alpha-synuclein (α-syn; encoded by gene SNCA), which is an intrinsically disordered protein belonging to the synuclein family, is a common biological factor in Parkinson’s disease and melanoma. Aggressive melanomas express high levels of α-syn, but the precise biological role of this protein in melanoma progression is not known. Our group has previously reported that α-syn promotes the release of extracellular vesicles (EVs) and regulates the trafficking of transferrin receptor in melanoma cells. During our studies of exosomal/EV markers, we found that CD81 and CD9, two key members of the tetraspanin family, were significantly downregulated in SK-MEL-28 SNCA-knock out clones compared to control cells. In contrast, a robust upregulation of CD63, another tetraspanin protein, was observed in SNCA-KO cells, which might be due to a compensatory mechanism for the downregulation of CD81 and CD9. CD81 and CD9 have been proposed as potential therapeutic targets, and CD63 was proposed as a positive prognostic marker in melanoma in numerous studies. Our group has previously shown that knocking out α-syn causes decreased tumor growth in vivo and in vitro. We hypothesize that α-syn regulates the levels of these tetraspanins, possibly by sorting into heterogeneous multivesicular bodies and modulating the exosomal secretion and lysosomal degradation of these proteins. This might be one of the principal mechanisms by which α-syn promotes progression of melanoma. We also have initial evidence from transmission electron microscopy (TEM) that depletion of α-syn causes the morphological alterations of plasma-membrane structure in melanoma cells, and it is known that CD9, CD81 and CD63 are important transmembrane proteins involved in membrane organization. This is the very first report of α-syn as a regulator of cellular homeostasis of CD9, CD81 and CD63, and further work is needed to understand the underlying mechanism. Citation Format: Nirjhar Mandal Aloy, Michael W. Graner, Stephan N. Witt. Alpha-synuclein may promote melanoma progression by modulating the levels of tetraspanin proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1357.
Abstract 2475: Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression
Authors: Sanjeev Shukla, Mohammed Al-Toubat, Allison H. Feibus, Ahmed Elshafei, Carlos Riveros, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, Adam M. Kase, John A. Copland III, Joachim L. Petit, Teruko Osumi, K.C. Balaji
Journal: Cancer Research (2023)

Abstract Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of protooncogene cellular myelocytomatosis (c- Myc) and other genes. Because c-Myc cannot be directly targeted by small molecular inhibitors due to disordered alpha helical structure, epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for diseases such as prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. We studied the efficacy of MT1, a novel bivalent BD inhibitor that is 100-fold more potent than the first in class BD inhibitor JQ1, at inhibiting PC growth. We tested the effect on viability by MT-1 on PC cell lines, 3D spheroids derived from clinically annotated drug resistant patient derived xenografts (PDX), mice PDX models and corroborated the molecular mechanism of MT1 down regulation of Myc leading to downstream Myc-dependent up regulation of Protein Kinase D1 (PrKD) substrate phosphorylation by western blot. MT-1 inhibited growth of PC in castration sensitive (LNCaP) and resistant PC cells (PC-3). MT-1 treatment upregulated PrKD expression and phosphorylation of known PrKD substrates: threonine 120 (Thr-120) residues in beta-catenin and the serine 216 in Cell Division Cycle 25 (CDC25C) in PC-3 cells. Moreover, MT-1 was effective in inhibition of 3D spheroids growth at IC 50 between 0.27-0.92µM in Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel metastatic castrate resistant PCa patient-derived tumor 3D spheroids. Additionally, MT1 was effective in inhibiting the tumor growth in PDX mice model. A combined intra-peritoneal administration of MT-1 with another c-Myc inhibitor (3JC48-3), an obligate c-Myc and MYC-associated protein X (MAX) heterodimerization inhibitor, increased the efficacy of inhibiting the PDX growth in mice. This study provides strong pre-clinical in vitro and in vivo evidence for advancing MT- 1 as a novel c-Myc targeting drug in PC. The MT-1 drug development will likely be highly impactful as c-Myc is dysregulated in three fourths of men with advanced PC. Citation Format: Sanjeev Shukla, Mohammed Al-Toubat, Allison H. Feibus, Ahmed Elshafei, Carlos Riveros, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, Adam M. Kase, John A. Copland III, Joachim L. Petit, Teruko Osumi, K.C. Balaji. Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2475.
Abstract 2003: Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma
Authors: Po-Fu Yueh, Yuan Chang, Keng-Li Lan, Fei-Ting Hsu
Journal: Cancer Research (2023)

Abstract Renal cell carcinoma (RCC) is one of the deadliest malignant tumors worldwide. The RCC’s standard treatments are including surgery, radiation, and chemotherapy. SUTENT® (sunitinib) was approved by US Food and Drug Administration (FDA) in 2016 to treat advanced RCC. According to the results from the clinical trial, sunitinib is associated with a higher objective response rate and survival rate than IFN-α, which indicates that it is an effective multiple tyrosine kinase inhibitor (TKi) against advanced RCC. Meanwhile, recent studies demonstrated sunitinib could cause tumor immune surveillance by upregulated autophagy to inhibit tumor PD-L1 expression. However, sunitinib targets not only tumor tissue but also multiple organs in the human body, which causes many serious side effects and even leads to death. In order to reduce the toxicity of sunitinib, our group design a novel nanocarrier by PEGylated liposome to encapsulate sunitinib (lipo-sunitinib). The PEGylated liposome could passively target tumor tissue by extravasation of nanoparticles through increased permeability of the tumor vasculature (enhanced permeability and retention, EPR effect). Moreover, the PEGylation on the liposome surface could prolong liposome half-life in the body through increased particle size. Through the EPR effect and PEGylation of lipo-sunitinib to target tumor cells precisely, we successfully increased RCC orthotopic tumor inhibition in mouse models compared with vehicle and sunitinib groups. Furthermore, the RCC tumor immunofluorescence staining revealed lipo-sunitinib had higher activated effector T cells (CD8+IL-2+IFN-γ+) and type 1 dendritic cells (CD11c+CD24+MHCII+) infiltration and lower vessel formation than sunitinib group. The flow cytometry also demonstrated that lipo-sunitinib had increased anti-tumor immune cells and inhibited immune suppressors in the systemic system. More importantly, lipo-sunitinib showed lower toxicity in mouse livers, hearts, and kidneys compared to the sunitinib group. Our results suggested lipo-sunitinib could inhibit tumor growth and prolong survival rate by modulating a positive anti-tumor microenvironment and anti-angiogenesis effects. In sum, with the polish of the delivery system, our novel nanodrug lipo-sunitinib could be a potential new treatment strategy for RCC patients. Citation Format: Po-Fu Yueh, Yuan Chang, Keng-Li Lan, Fei-Ting Hsu. Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2003.
Abstract 1228: TCF1 orchestrates the epithelial/mesenchymal hybrid phenotype in basal breast cancer via upregulation of FOXC2 leading to stemness and metastasis
Authors: Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Zuen Ren, Hao Wang, Larry Norton, Rachel Hazan
Journal: Cancer Research (2023)

Abstract The epithelial to mesenchymal transition (EMT) is a dynamic process driven by carcinoma cells undergoing partial and/or complete EMT, leading to tumor heterogeneity and malignancy. Here we show that TCF1, a TCF7 gene product, promotes an epithelial/mesenchymal hybrid (E/M) phenotype that was enriched in canonical Wnt signaling, stemness and metastatic properties. TCF1 knockdown in PyMT mammary tumor cells suppressed stemness and metastasis coincident with attenuation of the E/M phenotype in vivo. Interestingly, E/M cells (CD104highCD44high) isolated from human basal-like breast cancer cell lines, were enriched in TCF1, EMT and stemness markers relative to M cells (CD104 lowCD44high). In vivo, E/M cells showed dramatically increased tumorigenic, metastatic and organoid-forming potential as compared to M cells; which were in turn provoked by TCF1 overexpression in bulk mammary cancer cells. Remarkably, RNA sequencing unraveled striking upregulation of FOXC2 in E/M relative to M cells, which was suppressed by TCF1 inhibition. Moreover, FOXC2 knockdown in E/M cells destabilized the E/M state, whereas FOXC2 overexpression induced M to E/M transition. Together, these results demonstrate that TCF1 orchestrates the E/M state via upregulation of FOXC2, resulting in stemness and metastasis. Citation Format: Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Zuen Ren, Hao Wang, Larry Norton, Rachel Hazan. TCF1 orchestrates the epithelial/mesenchymal hybrid phenotype in basal breast cancer via upregulation of FOXC2 leading to stemness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1228.
Abstract 68: Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution
Authors: Liron Yoffe, Alain Borczuk, Timothy E. McGraw, Olivier Elemento, Nasser K. Altorki, Vivek Mittal
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide, largely due to diagnosis at advanced metastatic stages. Increased implementation of low-dose computed tomography (CT)-guided screening has led to the identification of non-solid lesions or ground-glass opacities (GGOs) that are not visible on plain chest radiography and can harbor very early-stage tumors. Growth of the lesions and/or development of a solid component can indicate more aggressive behavior. Using the low-dose CT reduced lung cancer mortality by &amp;gt;20%, underscoring the need for early detection and intervention. However, the cellular and molecular determinants that contribute to the malignant progression of those early preinvasive lesions remain poorly understood. To assess intratumoral heterogeneity and associated dynamic changes in the immune contexture during early lung carcinogenesis, we performed single-cell RNA-seq and Hyperion imaging on surgically resected freshly harvested tissues from 21 patients (matched solid and non-solid components of lesions and adjacent non-involved lungs), representing a spectrum from preneoplasia to invasive disease. Analysis of &amp;gt;300K cells identified cellular, transcriptomic, and metabolic alterations as well as tumor-stroma cross-talk pathways. Specifically, preinvasive to invasive disease progression was associated with significant changes in the immune landscape determined by an increase in exhausted CD4/CD8 T-cells, suppressive T-regs, polymorphonuclear myeloid-derived suppressor cells, and M2-like macrophages; and a decrease in cytotoxic CD8 T-cells, NK cells, and inflammatory cDC2 cells, suggesting that activation of immunosuppressive/anti-inflammatory microenvironment and suppression of immune activation microenvironment may enable tumor progression. Citation Format: Liron Yoffe, Alain Borczuk, Timothy E. McGraw, Olivier Elemento, Nasser K. Altorki, Vivek Mittal. Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 68.
Abstract 6703: Objective qualification of cell-free DNA by applying the cfDNA quality metric
Authors: Annika Dorn
Journal: Cancer Research (2023)

Abstract Next Generation Sequencing (NGS) of cell-free DNA (cfDNA) has the potential to reveal new biomarkers for various conditions. Despite the establishment of low input library protocols, library preparation of cfDNA samples remains a challenge due to restricted amount of starting material and variable size distribution of cfDNA fragments. The yield and quality of cfDNA can vary and a lot of care is required to obtain appropriate cfDNA starting material for downstream applications. Further, cfDNA samples may contain high molecular weight (HMW) DNA that can negatively affect library yield and sequencing quality. Therefore, quality control of cfDNA starting material is essential to ensure the success of downstream experiments. The Agilent Tapestation system with the Cell-free DNA ScreenTape Assay is based on automated electrophoresis and thereby offers an objective and reliable qualification of cfDNA samples by applying the %cfDNA quality score. By comparing different samples with varying total DNA yield and HMW contamination, the additional level of information gained by the %cfDNA score is highlighted. While other QC methods might miss critical information on HMW DNA contamination, this could result in flawed yield estimations, ultimately threatening the successful outcome of downstream experiments. Therefore, accurate quantification of cfDNA starting material, taking also HMW DNA contamination into account is essential for NGS library preparation and generating reliable NGS results. Citation Format: Annika Dorn. Objective qualification of cell-free DNA by applying the cfDNA quality metric [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6703.